The long-term goal of this project is to determine mechanisms by which synaptic transmission is regulated by cellular stress pathways. The motivation of this project is twofold. First, stress plays a critical role in cognitive dysfunction and neurodegeneration associated with neurodegenerative diseases. Second, although much has been learned about how cellular responses to stress can promote neuronal survival, far less is known about how these responses can regulate neuronal function. We propose to characterize the role of a stress response pathway that mediates cellular responses to oxidative stress in regulating synaptic function using C. elegans as a model system. We previously identified a new protein that is conserved in vertebrates, WDR-23, in a functional genomic screen for genes required for synaptic transmission at the neuromuscular junction. We found that WDR-23 promotes the secretion of neurotransmitter from presynaptic terminals by antagonizing the activity of the transcription factor SKN-1. SKN-1 is the ortholog of the mammalian NF-E2 related factor (Nrf) family of transcription factors, which are critical for protecting neurons form the neurodegenerative effects of oxidative stress. We found that skn-1 activity is required for proper neurotransmission and for expression of a neuron-specific gene, acr-2, which encodes an acetylcholine receptor subunit of unknown function. Here we propose to test the hypothesis that SKN-1 regulates synaptic transmission in response to stress. First, we will determine how SKN-1 activity is negatively regulated by WDR-23 and by stress pathways in neurons. Second, we will identify the environmental and cellular stress pathways that activate SKN-1 in neurons. Third, we will determine how SKN-1-activated transcriptional programs generate changes in neurotransmitter secretion and synaptic function. These experiments will provide insights into the molecular mechanisms by which the SKN-1/Nrf stress response pathway regulates synaptic function. In summary, this work will establish a novel role for SKN-1/Nrf-mediated transcriptional programs in regulating synaptic transmission, and should provide insights into how stress impacts synaptic dysfunction associated with neurodegenerative diseases. PUBLIC HEALTH RELEVANCE: Many neurodegenerative disorders, such as Alzheimer's and Parkinson's disease are thought to be caused by toxins that accumulate in brain cells as the result of normal ageing. Here we propose to study how a natural system that the body uses to remove these toxins can impact normal brain cell function, and how it can be used to delay or prevent the onset of these diseases.